Skip to main content

Some NLM-NCBI services and products are experiencing heavy traffic, which may affect performance and availability. We apologize for the inconvenience and appreciate your patience. For assistance, please contact our Help Desk at info@ncbi.nlm.nih.gov.

Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1990 Aug;10(8):4170–4179. doi: 10.1128/mcb.10.8.4170

The Wnt-1 (int-1) oncogene promoter and its mechanism of activation by insertion of proviral DNA of the mouse mammary tumor virus.

R Nusse 1, H Theunissen 1, E Wagenaar 1, F Rijsewijk 1, A Gennissen 1, A Otte 1, E Schuuring 1, A van Ooyen 1
PMCID: PMC360946  PMID: 1695322

Abstract

Wnt-1 (int-1) is a cellular oncogene often activated by insertion of proviral DNA of the mouse mammary tumor virus. We have mapped the 5' end and the promoter area of the Wnt-1 gene by nuclease protection and primer extension assays. In differentiating P19 embryonal carcinoma cells, in which Wnt-1 is naturally expressed, two start sites of transcription were found, one preceded by two TATA boxes and one preceded by several GC boxes. In P19 cells, a 1-kilobase upstream sequence of Wnt-1 was able to confer differentiation-specific expression on a heterologous gene. We have investigated how Wnt-1 transcription was affected by mouse mammary tumor virus proviral integrations in various configurations near the promoters of the gene. One provirus has been inserted in the 5' nontranslated part of Wnt-1, in the same transcriptional orientation, and has functionally replaced the Wnt-1 promoters. Wnt-1 transcription in this tumor starts in the right long terminal repeat of the provirus, with considerable readthrough transcription from the left long terminal repeat. Another provirus has been inserted in the orientation opposite that of Wnt-1 into a GC box, disrupting the first Wnt-1 transcription start site but not the downstream start site. Most insertions have not structurally altered the Wnt-1 transcripts and have enhanced the activity of the normal two promoters.

Full text

PDF
4170

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barrera-Saldana H., Takahashi K., Vigneron M., Wildeman A., Davidson I., Chambon P. All six GC-motifs of the SV40 early upstream element contribute to promoter activity in vivo and in vitro. EMBO J. 1985 Dec 30;4(13B):3839–3849. doi: 10.1002/j.1460-2075.1985.tb04156.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brown A. M., Wildin R. S., Prendergast T. J., Varmus H. E. A retrovirus vector expressing the putative mammary oncogene int-1 causes partial transformation of a mammary epithelial cell line. Cell. 1986 Sep 26;46(7):1001–1009. doi: 10.1016/0092-8674(86)90699-9. [DOI] [PubMed] [Google Scholar]
  3. Cullen B. R., Lomedico P. T., Ju G. Transcriptional interference in avian retroviruses--implications for the promoter insertion model of leukaemogenesis. Nature. 1984 Jan 19;307(5948):241–245. doi: 10.1038/307241a0. [DOI] [PubMed] [Google Scholar]
  4. Davis C. A., Joyner A. L. Expression patterns of the homeo box-containing genes En-1 and En-2 and the proto-oncogene int-1 diverge during mouse development. Genes Dev. 1988 Dec;2(12B):1736–1744. doi: 10.1101/gad.2.12b.1736. [DOI] [PubMed] [Google Scholar]
  5. Edwards M. K., McBurney M. W. The concentration of retinoic acid determines the differentiated cell types formed by a teratocarcinoma cell line. Dev Biol. 1983 Jul;98(1):187–191. doi: 10.1016/0012-1606(83)90348-2. [DOI] [PubMed] [Google Scholar]
  6. Fung Y. K., Shackleford G. M., Brown A. M., Sanders G. S., Varmus H. E. Nucleotide sequence and expression in vitro of cDNA derived from mRNA of int-1, a provirally activated mouse mammary oncogene. Mol Cell Biol. 1985 Dec;5(12):3337–3344. doi: 10.1128/mcb.5.12.3337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gorman C. M., Rigby P. W., Lane D. P. Negative regulation of viral enhancers in undifferentiated embryonic stem cells. Cell. 1985 Sep;42(2):519–526. doi: 10.1016/0092-8674(85)90109-6. [DOI] [PubMed] [Google Scholar]
  9. Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
  10. Herman S. A., Coffin J. M. Differential transcription from the long terminal repeats of integrated avian leukosis virus DNA. J Virol. 1986 Nov;60(2):497–505. doi: 10.1128/jvi.60.2.497-505.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Herman S. A., Coffin J. M. Efficient packaging of readthrough RNA in ALV: implications for oncogene transduction. Science. 1987 May 15;236(4803):845–848. doi: 10.1126/science.3033828. [DOI] [PubMed] [Google Scholar]
  12. Ingham P. W., Baker N. E., Martinez-Arias A. Regulation of segment polarity genes in the Drosophila blastoderm by fushi tarazu and even skipped. Nature. 1988 Jan 7;331(6151):73–75. doi: 10.1038/331073a0. [DOI] [PubMed] [Google Scholar]
  13. Ingham P. W. The molecular genetics of embryonic pattern formation in Drosophila. Nature. 1988 Sep 1;335(6185):25–34. doi: 10.1038/335025a0. [DOI] [PubMed] [Google Scholar]
  14. Jakobovits A., Shackleford G. M., Varmus H. E., Martin G. R. Two proto-oncogenes implicated in mammary carcinogenesis, int-1 and int-2, are independently regulated during mouse development. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7806–7810. doi: 10.1073/pnas.83.20.7806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kawasaki E. S., Clark S. S., Coyne M. Y., Smith S. D., Champlin R., Witte O. N., McCormick F. P. Diagnosis of chronic myeloid and acute lymphocytic leukemias by detection of leukemia-specific mRNA sequences amplified in vitro. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5698–5702. doi: 10.1073/pnas.85.15.5698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Krimpenfort P., de Jong R., Uematsu Y., Dembic Z., Ryser S., von Boehmer H., Steinmetz M., Berns A. Transcription of T cell receptor beta-chain genes is controlled by a downstream regulatory element. EMBO J. 1988 Mar;7(3):745–750. doi: 10.1002/j.1460-2075.1988.tb02871.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Linney E., Davis B., Overhauser J., Chao E., Fan H. Non-function of a Moloney murine leukaemia virus regulatory sequence in F9 embryonal carcinoma cells. 1984 Mar 29-Apr 4Nature. 308(5958):470–472. doi: 10.1038/308470a0. [DOI] [PubMed] [Google Scholar]
  18. Maxam A. M., Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. doi: 10.1016/s0076-6879(80)65059-9. [DOI] [PubMed] [Google Scholar]
  19. Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. doi: 10.1093/nar/12.18.7035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Myers R. M., Larin Z., Maniatis T. Detection of single base substitutions by ribonuclease cleavage at mismatches in RNA:DNA duplexes. Science. 1985 Dec 13;230(4731):1242–1246. doi: 10.1126/science.4071043. [DOI] [PubMed] [Google Scholar]
  21. Nusse R., Varmus H. E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell. 1982 Nov;31(1):99–109. doi: 10.1016/0092-8674(82)90409-3. [DOI] [PubMed] [Google Scholar]
  22. Nusse R., van Ooyen A., Cox D., Fung Y. K., Varmus H. Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15. Nature. 1984 Jan 12;307(5947):131–136. doi: 10.1038/307131a0. [DOI] [PubMed] [Google Scholar]
  23. Rijsewijk F. A., van Lohuizen M., van Ooyen A., Nusse R. Construction of a retroviral cDNA version of the int-1 mammary oncogene and its expression in vitro. Nucleic Acids Res. 1986 Jan 24;14(2):693–702. doi: 10.1093/nar/14.2.693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rijsewijk F., Schuermann M., Wagenaar E., Parren P., Weigel D., Nusse R. The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless. Cell. 1987 Aug 14;50(4):649–657. doi: 10.1016/0092-8674(87)90038-9. [DOI] [PubMed] [Google Scholar]
  25. Rijsewijk F., van Deemter L., Wagenaar E., Sonnenberg A., Nusse R. Transfection of the int-1 mammary oncogene in cuboidal RAC mammary cell line results in morphological transformation and tumorigenicity. EMBO J. 1987 Jan;6(1):127–131. doi: 10.1002/j.1460-2075.1987.tb04729.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Robinson H. L., Gagnon G. C. Patterns of proviral insertion and deletion in avian leukosis virus-induced lymphomas. J Virol. 1986 Jan;57(1):28–36. doi: 10.1128/jvi.57.1.28-36.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Rubin M. R., Toth L. E., Patel M. D., D'Eustachio P., Nguyen-Huu M. C. A mouse homeo box gene is expressed in spermatocytes and embryos. Science. 1986 Aug 8;233(4764):663–667. doi: 10.1126/science.3726554. [DOI] [PubMed] [Google Scholar]
  28. Schuuring E., van Deemter L., Roelink H., Nusse R. Transient expression of the proto-oncogene int-1 during differentiation of P19 embryonal carcinoma cells. Mol Cell Biol. 1989 Mar;9(3):1357–1361. doi: 10.1128/mcb.9.3.1357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Serfling E. Autoregulation--a common property of eukaryotic transcription factors? Trends Genet. 1989 May;5(5):131–133. doi: 10.1016/0168-9525(89)90049-8. [DOI] [PubMed] [Google Scholar]
  30. Shackleford G. M., Varmus H. E. Expression of the proto-oncogene int-1 is restricted to postmeiotic male germ cells and the neural tube of mid-gestational embryos. Cell. 1987 Jul 3;50(1):89–95. doi: 10.1016/0092-8674(87)90665-9. [DOI] [PubMed] [Google Scholar]
  31. St-Arnaud R., Craig J., McBurney M. W., Papkoff J. The int-1 proto-oncogene is transcriptionally activated during neuroectodermal differentiation of P19 mouse embryonal carcinoma cells. Oncogene. 1989 Sep;4(9):1077–1080. [PubMed] [Google Scholar]
  32. Swanstrom R., Parker R. C., Varmus H. E., Bishop J. M. Transduction of a cellular oncogene: the genesis of Rous sarcoma virus. Proc Natl Acad Sci U S A. 1983 May;80(9):2519–2523. doi: 10.1073/pnas.80.9.2519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Tsukamoto A. S., Grosschedl R., Guzman R. C., Parslow T., Varmus H. E. Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell. 1988 Nov 18;55(4):619–625. doi: 10.1016/0092-8674(88)90220-6. [DOI] [PubMed] [Google Scholar]
  34. Varmus H. E. The molecular genetics of cellular oncogenes. Annu Rev Genet. 1984;18:553–612. doi: 10.1146/annurev.ge.18.120184.003005. [DOI] [PubMed] [Google Scholar]
  35. Wasylyk B., Wasylyk C., Augereau P., Chambon P. The SV40 72 bp repeat preferentially potentiates transcription starting from proximal natural or substitute promoter elements. Cell. 1983 Feb;32(2):503–514. doi: 10.1016/0092-8674(83)90470-1. [DOI] [PubMed] [Google Scholar]
  36. Westaway D., Goodman P. A., Mirenda C. A., McKinley M. P., Carlson G. A., Prusiner S. B. Distinct prion proteins in short and long scrapie incubation period mice. Cell. 1987 Nov 20;51(4):651–662. doi: 10.1016/0092-8674(87)90134-6. [DOI] [PubMed] [Google Scholar]
  37. Wilkinson D. G., Bailes J. A., McMahon A. P. Expression of the proto-oncogene int-1 is restricted to specific neural cells in the developing mouse embryo. Cell. 1987 Jul 3;50(1):79–88. doi: 10.1016/0092-8674(87)90664-7. [DOI] [PubMed] [Google Scholar]
  38. Wolgemuth D. J., Viviano C. M., Gizang-Ginsberg E., Frohman M. A., Joyner A. L., Martin G. R. Differential expression of the mouse homeobox-containing gene Hox-1.4 during male germ cell differentiation and embryonic development. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5813–5817. doi: 10.1073/pnas.84.16.5813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. van Ooyen A., Kwee V., Nusse R. The nucleotide sequence of the human int-1 mammary oncogene; evolutionary conservation of coding and non-coding sequences. EMBO J. 1985 Nov;4(11):2905–2909. doi: 10.1002/j.1460-2075.1985.tb04021.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. van Ooyen A., Nusse R. Structure and nucleotide sequence of the putative mammary oncogene int-1; proviral insertions leave the protein-encoding domain intact. Cell. 1984 Nov;39(1):233–240. doi: 10.1016/0092-8674(84)90209-5. [DOI] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES